Protein aspartate ph0sphatases control the output of tw0-c0mp0nent signal transducti0n systems

REVIEWS A microorganism in its natural habitat is bombarded with information from its environment that it must iden- tify and respond to in order to maximize its chances of survival. Two-component systems are sensory, recog- nition and signal transduction systems, which allow an organism to process and respond to a multitude of sig- nals rapidly Signal tmn~ u-t on is accomplished by a sensor kinase (the first component) and tbe end prod- uct of this process is, usually, an autophosphorylated histidine I. The phosphorylated kinase is recognized by a specific response regulator (the ~cond component) to which the phosphate is transferred, thus activating the particular response regulator. The level of phos- phorylation of the response regulator is controlled by opposing kinase and phosphatase activities that are usually inherent in the sensor kinase protein. In more complex systems, such as cheraotaxis, the activities are on separate proteins. For example, during sporalation of Bacillus species multiple phosphatases and multiple kinases affect the phosphorylation level. In most two- component systems, the phosphorylated response regulator is a transcription factor for genes encoding proteins that are involved with the original signal that activates the .system. There are many variations on this theme that generally add one or more kinases, or recep- tors; or add more response regulators, to customize the signal transduction pathway for a specific purlx~se. In the course of evolution, microorganisms, as well as fungi and plants >~, have adapted this efficient mecha- nism in order to carry out a wide variety of cellular recognition functions ~.¢'. Histidine-kinase-based two-component systems The key element in two-component signal transduc- tion is the sensor kinase or histidine kinase. Sensing the presence or absence of a variety of proteins, chemicals or effectors occurs, in many cases, by ligand interaction with a binding protein or receptor. This property is nor- mally the province of the N-terminal region of the pro- tein that shows little or no amino acid conservation from kinase to kinase, as expected of proteins that bind different ligands. Conversely, there are several distinct conserved raotifs on the carboxyl portion of the protein, which contains the kinase activity. The most amino- proximal of these is the histidine motif (the site of phos- phorylation), followed by several short motifs, which, together, comprise the nucleotide-binding site 6. The sites of specificity for the response regulator, which accepts phosphate from the histidine site, have not been determined, but such sites might not be expected to show conservation from kinase to kinase. The kinase domain has three generally accepted functions: (1) amophosphorylation of the histidine with ATP; (2) phosphotransfer from the kinase to an aspar- tate of the response regulator; and (3) phosphotransfer from aspartyl phosphate back to ADP or to water (i.e. phosphatase activity). In response to ligand bind- ing, the sensor domain of the molecule modifies its kinase:phosphatase-activity ratio. By modifying this ratio, the kinase is able to adjust the phosphorylation level of the response regulator so that it reflects the level of signal input, regardless of whether it increases or decreases. Some signal transduction systems opera; e